Young men who have sex with men (YMSM) continue to bear the burden of HIV infection in the United States. Public health programs supporting pre-exposure prophylaxis (PrEP) with daily oral emtricitabine/tenofovir disoproxil fumarate (FTC/TDF) are increasingly being adopted as a critical element to confront the HIV epidemic. However, the effectiveness of PrEP is highly dependent on an individual's sustained adherence to the medication. Laboratory-based drug levels collected in PrEP clinical trials have correlated poorly with routine measures of adherence, including pill count, pharmacy refill records, and self-report. Discrepancies in adherence exist even among populations who express a strong willingness to accept PrEP and occur in spite of comprehensive risk reduction and adherence counseling; these discrepancies appear most problematic among youth who are at greatest risk for HIV. These difficulties impact clinical trial outcomes as well as real world implementation, underscoring the need for innovative and validated tools to measure adherence. This application directly investigates new approaches to rapidly and accurately assess adherence by evaluating an integrated technology system that confirms ingestion of oral PrEP, monitors adherence both in real-time and longitudinally, and provides visual feedback mechanisms to promote enhanced adherence behaviors. We propose to evaluate the pharmacokinetics (PK), safety, feasibility and acceptability of the Proteus Sensor System (PSS), a novel FDA-approved system for detecting the ingestion of a pharmaceutical drug. In this developmental study, we will confirm the bioequivalence of FTC/TDF with and without the PSS through dissolution testing followed by PK testing with 24 low-risk participants. We will then evaluate the PSS with FTC/TDF using a 2-arm trial with a crossover design to assess the feasibility and acceptability of the PSS to monitor PrEP adherence over 24 weeks among a sample of 100 YMSM, ages 16-24 years, who are at risk for HIV acquisition. Finally, we will qualitatively explore the acceptability of each component of the PSS (i.e. encapsulated tablet, wearable patch, mobile device/visual feedback) through in-depth interviews as well as age-stratified focus group discussions (16-19 vs. 20-24). We hypothesize that adherence detected by the ingestible sensor system will correlate with estimated weekly FTC/TDF tablet use measured by FTC- triphosphate and TFV-diphosphate levels in dried blood spots, and that YMSM will exhibit greater adherence to FTC/TDF PrEP during the implementation of the PSS compared to standard-of-care PrEP over 24 weeks.